AChE inhibitors and substrates (Part III)

AChE monovalent inhibitors (continuation of the pages AChE inhibitors and substrates and AChE inhibitors and substrates (Part II))


Galanthamine iminium derivative
The X-ray structure of TcAChE in complex with galanthamine iminium derivative (compound 5) was determined at 2.05 Å resolution (1w6r). The binding mode of this compound (cyan) with TcAChE is virtually identical to that of galanthamine (red) itself (1dx6). The TcAChE residues which interact with galanthamine in the galanthamine/TcAChE complex are colored pink, while those of compound 5/TcAChE are in lime. The main structural change is the side-chain movement of Phe330 in compound 5/TcAChE complex, in comparison to that of galanthamine. Compound 5 differs from galanthamine by the presence of quaternary nitrogen atom (N+; blue) instead N of galanthamine. This chemical difference causes the structural change in TcAChE and the slight decrease in affinity of compound 5 to TcAChE in comparison to galanthamine.

Rivastigmine
Rivastigmine (Exelon) is a carbamate inhibitor of AChE, and it is currenly used in therapy of Alzheimer's disease. Rivastigmine (Exelon) (colored yellow) interacts with TcAChE (colored lime) at the active-site gorge (1gqr). The carbamyl moiety of rivastigmine is covalently bound to the active-site S200 Oγ. The second part of rivastigmine (the leaving group), NAP ((−)-S-3-[1-(dimethylamino)ethyl]phenol) is also held in the active-site gorge, but it is separated from the carbamyl moiety, hence, carbamylation took place. The crystal structure of TcAChE/<font color='magenta'>NAP (colored magenta) is known (1gqs). The <font color='violet'>TcAChE active-site residues which are interacting with NAP are <font color='violet'>colored violet. NAP is located in a similar region of TcAChE active site, but with different orientation than that of the NAP part (colored yellow) in the TcAChE/rivastigmine complex. Only H440 and F330 significantly change their side-chain conformations. <scene name='1gqr/Active_site/8'>Overlap of the TcAChE active sites in 4 different structures (<font color='lime'>TcAChE /rivastigmine (1gqr), <font color='violet'>TcAChE /<font color='magenta'>NAP (1gqs), <font color='cyan'>native TcAChE (2ace), and TcAChE/VX (1vxr, TcAChE colored white and VX black) reveals that the conformation of H440 in the TcAChE/NAP structure is very similar its conformation in the native TcAChE (2ace), but the distance between H440 Nδ and E327 Oε is significantly longer in the TcAChE/rivastigmine and the TcAChE/VX complexes. This structural change disrupts the catalytic triad consisting of S200, E327, H440. This could explain the very slow kinetics of AChE reactivation after its inhibition by rivastigmine.

Thioflavin T
The TcAChE active site consists of two binding subsites. One of them is the "catalytic anionic site" (CAS), which involves the catalytic triad <scene name='2j3q/Active_site/2'>Ser200, His440, and Glu327 <font color='orange'>(colored orange) and the conserved residues <scene name='2j3q/Active_site/3'>Trp84 and Phe330 which also participate in ligand recognition. Another conserved residue <scene name='2j3q/Active_site/4'>Trp279 <font color='cyan'>(colored cyan) is situated at the second binding subsite, termed the "peripheral anionic site" (PAS), ~14 Å from CAS. <scene name='2j3q/Active_site/6'>Thioflavin T is a good example of the PAS-binding AChE inhibitors. <scene name='2j3q/Active_site/7'>Superposition of the crystal structure of the <font color='red'>edrophonium /TcAChE (mentioned above as a CAS-binding inhibitor) (2ack) on the <font color='magenta'>thioflavin T /TcAChE complex structure (2j3q) shows that these ligands' positions do not overlap. Of note is that Phe330, which is part of the CAS, is the single residue interacting with <font color='magenta'>thioflavin T. This residue is the only one which significantly <scene name='2j3q/Active_site/9'>changes its conformation to avoid clashes in comparison to other CAS residues of the <font color='red'>edrophonium /TcAChE complex.

OTMA
OTMA is a nonhydrolyzable substrate analogue of AChE. Its hydrolysis is impossible as <scene name='2vja/Common/3'>OTMA possesses <scene name='2vja/Common/4'>carbon atom instead of the <scene name='2vja/Common/5'>ester oxygen in the AChE natural substrate ACh. Similarly to ACh, OTMA covalently binds to the TcAChE (2vja) <scene name='2vja/Active_site/1'>Ser200 Oγ at the CAS. At this subsite OTMA also interacts with <scene name='2vja/Active_site/2'>Trp84, Phe330 (cation-π interactions); <scene name='2vja/Active_site/3'>Glu199 (electrostatic interaction); <scene name='2vja/Active_site/4'>Gly118, Gly119, and Ala201 (hydrogen bonds). OTMA binds not only at CAS, but also at PAS. A second OTMA molecule interacts with <scene name='2vja/Active_site/5'>Trp279, Tyr70 (cation-π interactions), and <scene name='2vja/Active_site/6'>Tyr121 (weak hydrogen bond). Thus, this dual binding mode of OTMA with TcAChE (to CAS and PAS) could be prototypical for AChE bivalent inhibitors. </StructureSection>

Additional Resources
For additional information, see: Alzheimer's Disease

Please see also our pages AChE bivalent inhibitors and AChE bivalent inhibitors (Part II).